Zinc Prevents DNA Damage in Normal Cells but Shows Genotoxic and Cytotoxic Effects in Acute Myeloid Leukemia Cells.

Maria Inês Costa,Joana Jorge,Ana Cristina Gonçalves,Raquel Alves,Ana Bela Sarmento-Ribeiro,Isabel Marques Carreira,Beatriz Santos Lapa

doi:10.3390/ijms23052567

Abstract

Genomic instability is prevented by the DNA damage response (DDR). Micronutrients, like zinc (Zn), are cofactors of DDR proteins, and micronutrient deficiencies have been related to increased cancer risk. Acute myeloid leukemia (AML) patients commonly present Zn deficiency. Moreover, reports point to DDR defects in AML. We studied the effects of Zn in DDR modulation in AML. Cell lines of AML (HEL) and normal human lymphocytes (IMC) were cultured in standard culture, Zn depletion, and supplementation (40 μM ZnSO4) conditions and exposed to hydrogen peroxide (H2O2) or ultraviolet (UV) radiation. Chromosomal damage, cell death, and nuclear division indexes (NDI) were assessed through cytokinesis-block micronucleus assay. The phosphorylated histone H2AX (yH2AX) expression was monitored at 0 h, 1 h, and 24 h after exposure. Expression of DDR genes was evaluated by quantitative real time polymerase chain reaction (qPCR). Zn supplementation increased the genotoxicity of H2O2 and UV radiation in AML cells, induced cytotoxic and antiproliferative effects, and led to persistent yH2AX activation. In contrast, in normal lymphocytes, supplementation decreased damage rates, while Zn depletion favored damage accumulation and impaired repair kinetics. Gene expression was not affected by Zn depletion or supplementation. Zn presented a dual role in the modulation of genome damage, preventing damage accumulation in normal cells and increasing genotoxicity and cytotoxicity in AML cells.

Highlights

In the Acute myeloid leukemia (AML) cell line, HEL, no significant differences in damage rates were noticed between ZnS and Std conditions (Figure 1B)
The importance of Zn for human health is reflected by the variety of functions in which it is implicated and the large spectrum of conditions resulting from Zn deficiency [9,14]
In AML and other malignancies, decreases in serological or cellular Zn have been proposed as an adaptive mechanism of cells to avoid the cytoprotective effects of Zn and to acquire the biological advantages that allow malignant transformation [9,14,15,16]

Summary

Introduction

Genome integrity is assured by several signaling molecules, sensors, mediators, transducers, and effector proteins that cooperate to eliminate or minimize DNA damage. [1,2] These complex protein networks constitute the DNA damage response (DDR). Many micronutrients are substrates and cofactors of key DDR reactions, meaning that their bioavailability is critical for damage recognition and repair [2,3,4,5]. Zn ions associated with proteins influence processes such as antioxidant defenses, DNA replication, transcription, translation, DNA repair, chromatin structure, proliferation, maturation, immune responses, and cell death [6,7,8,9].

Objectives

Methods

Results

Conclusion